Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7-3-phenly-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (actorvastatin)

ABSTRACT

A method of manufacturing an amorphous form of the hemi-calcium salt of (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid of formula (I), in which (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid or its salt with a cation M +  wherein M 30   is either a cation of an alkali metal or an ammonium cation of formula R n N (+) H (4−n)  wherein R is lower C 1 -C 5  alkyl, n may reach values ranging between 0 and 3, is, without isolating the intermediate in the form of the hemi-calcium salt or of another salt, acid or lactone, converted, in a solution, by the treatment with the calcium salt or calcium hydroxide, or a calcium C 1 -C 5  alcoholate, to the hemi-calcium salt, and the latter is precipitated with a C 1 -C 5 hydrocarbon or dialkylether of formula R 1 OR 2 , wherein each of R 1  and R 2  is a C 1 -C 5  alkyl group. The starting acid or its salt is prepared starting from (3R, 5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)acetate of formula II.

TECHNICAL FIELD

The invention relates to a new method of manufacturing an amorphous formof the hemi-calcium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid, known under the non-proprietary name atorvastatin. The said drugis an important representative of hypolipidemic and hypocholestericmedicaments.

BACKGROUND ART

Atorvastatin (formula I) is manufactured according to published patents(U.S. Pat. Nos. 4,681,893; 5,003,080; 5,097,045; 5,103,024; 5,124,482;5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995;5,397,792; 5,342,952) usually from the sodium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid and a suitable, water soluble calcium salt, preferably from calciumacetate or chloride.

The starting sodium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid may be obtained from the said acid, which is normally obtained from(3R,5R) tert-butyl(6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)-acetate(formula II).

This key intermediate is converted to the sodium salt of the respectiveacid first by mixing with hydrochloric acid and, later on, with a largeexcess of sodium hydroxide, which is, however, accompanied with a largeamount of excess hydroxide and also of sodium chloride. Acidificationfollowed by extraction then affords a solution of the respective acid(formula III) without any inorganic impurities. Thus obtained acid isthen converted to the respective lactone (formula IV), which can bepurified by crystallization, and the purified lactone is then convertedto the sodium salt by mixing with an equivalent of sodium hydroxide; anexcess cannot be used as it would form, with the calcium salt, calciumhydroxide in the next step that could not be fully removed from theproduct in the follow up process steps according to the above patents.However, when an equivalent of the hydroxide is used the reaction istime consuming and it has to be monitored by HPLC. Another disadvantageof this process is loss of approximately 20% of the yield.

Depending on the mode of carrying out, atorvastatin is obtained in someof its crystalline forms or as amorphous atorvastatin. In the originalpatents (for instance U.S. Pat. Nos. 4,681,893 and 5,273,995) there isno mention on the form of the substance obtained under these patents.Later patents (U.S. Pat. Nos. 5,969,156 and 6,121,461), disclosingcrystalline forms of atorvastatin, suggest that the substance obtainedaccording to the original patents was amorphous. Patent EP 839,132,disclosing a new method of obtaining the amorphous form of atorvastatinby dissolving crystalline atorvastatin of form I in a non-hydroxylatedsolvent (the patent mentions tetrahydrofuran and a mixture oftetrahydrofuran and toluene as examples of such solvents) followed bydrying, repeats again that the original patents result in amorphousatorvastatin, but that such method is difficult to reproduce. Accordingto our experience, atorvastatin obtained according to previous patents(U.S. Pat. Nos. 4,681,893, 5,298,627 and 5,273,995) is not perfectlyamorphous and according to an X-ray analysis it shows the presence ofcrystalline components (see FIG. 1). The original patent U.S. Pat. No.4,681,893 also describes a possibility of the purification of theunsuitable substance by dissolving in ethyl acetate, filtration throughsupercel and precipitation of the solution with hexane at 50° C. Apatent to Ranbaxy Laboratories (WO 00/71116 A1) discloses conversion ofthe crystalline form of atorvastatin in a non-hydroxylated solvent andprecipitation of the resulting solution with a non-polar hydrocarbonsolvent. A similar approach is described in a patent to Lek (WO 01/42209A1), which describes conversion of the crystalline form of atorvastatinto the amorphous form by dissolving in a variety of solvents includingboth non-hydroxylated solvents and lower alcohols, followed byprecipitation of these solutions with solvents in which atorvastatin isinsoluble. Again, such solvents are broadly defined and, in addition tonon-polar hydrocarbon solvents, they include aliphatic ethers.

The objective of this invention is to describe a new improved method ofmanufacturing an amorphous form of the hemi-calcium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid that would not show the disadvantages of the above mentionedprocesses.

DISCLOSURE OF THE INVENTION

The benefits of the amorphous atorvastatin for some applications werestressed in the above-mentioned patent EP 839,132. The subject-matter ofthe present invention is a new method of manufacturing an amorphous formof the hemi-calcium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid, consisting in conversion of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid or its salt containing cation M⁺ wherein M⁺ is either an alkalimetal cation or an ammonium cation of formula R_(n)N⁽⁺⁾H_((4−n)) whereinR is a lower alkyl C₁-C₅, n may reach values ranging between 0 and 3,without isolating the intermediate in the form of the hemi-calcium saltor of another salt, acid or lactone, in a solution by the treatment of acalcium salt or of calcium hydroxide, or of a calcium C₁-C₅ alcoholate,to the hemi-calcium salt, followed by the precipitation thereof with aC₅-C₁₂ hydrocarbon or a dialkylether of formula R₁OR₂, wherein each ofR₁ and R₂ is a C₁-C₅ alkyl group, thus forming a solid amorphous phase.

The whole process as above is based on a surprising finding that inethyl acetate and in some related solvents not only the free acidcorresponding to atorvastatin, but also a number of its salts, forinstance the sodium salt, the potassium salt, ammonium salts derivedfrom ammonia, primary, secondary and tertiary amines, and also thehemi-calcium salt itself are easily soluble.

A more detailed description of the invention follows.

The amorphous form of atorvastatin is preferably obtained directly byprecipitation of a solution of the hemi-calcium salt of atorvastatin ina suitable solvent, preferably in an ester of a C₁-C₅ acid and a C₁-C₅alcohol, using ethyl acetate being particularly advantageous, with anon-polar solvent, preferably with pentane, hexane, heptane orcyclohexane, optionally with a dialkylether R₁OR₂ wherein each of R₁ andR₂ is a C₁-C₅ alkyl group, preferably with diethylether,diisopropylether or t-butyl-methylether. In order to increase purity ofthe product it has been proven as useful to dilute the atorvastatinsolution in ethyl acetate, prior to precipitation, with an additionalco-solvent, for instance toluene, tert-butylmethylether ortetrahydrofuran, in an amount of from 5 to 95%, preferably from 30 to70%. The amorphous form can also be obtained using a reversed process,wherein a solution of the hemi-calcium salt in a suitable solvent isadded to one of the above-mentioned non-polar solvents. In none of theprevious stages of this process, the hemi-calcium salt is not isolatedin the solid state and, therefore, none of the patents protectingindividual crystalline forms of this substance or processes ofconversion of crystalline atorvastatin to amorphous atorvastatin can beinfringed.

The solution of the hemi-calcium salt of atorvastatin in a suitablesolvent, preferably in an ester of a C₁-C₅ acid and a C₁-C₅ alcohol,more preferably in ethyl acetate, can be obtained from a solution of thecorresponding free acid, obtained using the previously described methodfrom intermediate II. This solution is converted to the solution of thehemi-calcium salt by shaking with an aqueous solution of calciumhydroxide, with a suspension of calcium hydroxide in a smaller amount ofwater or, optionally, with a solution of a calcium C₁-C₅ alcoholate in asuitable solvent, preferably in the respective alcohol. Anotherpossibility is to use a solution of any of the above salts ofatorvastatin in a suitable solvent, preferably in ethyl acetate, and toconvert it to a solution of the hemi-calcium salt of atorvastatin byshaking with a suitable water soluble calcium salt, preferably withcalcium acetate. The excess of the used salts can then be simply removedby washing of the organic solution of the hemi-calcium salt ofatorvastatin with water or with some aqueous solutions, for instancebrine, and subsequently with water. Depending on the used precipitationsystem and the precipitation method, the solution of the hemi-calciumsalt of atorvastatin will be then used in the next step without dryingor it may be pre-dried with a suitable desiccant, preferably withsodium, calcium or magnesium sulphates.

Suitable water-soluble salts of atorvastatin can be advantageouslyobtained from a solution of the corresponding free acid obtained usingthe previously described method from the intermediate of formula II.This solution is then converted to the respective salt by adding asolution of an alkali hydroxide in water, by adding a solution ofammonia in water or a solution of the respective amine in water,followed by shaking. Preferably, amines such as triethylamine that areliquid at the normal temperature are used, which can be added to thesolution of the respective free acid without using a solvent. Thesolutions of the above salts obtained in this way can be used directly,without any purification, for conversion to the solution of thehemi-calcium salt of atorvastatin as described above. The solutions ofsome of the above salts of atorvastatin can also be evaporated in thisstage and purified by crystallization in suitable solvents. A solutionof the sodium or potassium salts of atorvastatin can be advantageouslyobtained also directly from the solution after processing of thereaction of conversion of the intermediate of formula II. In the finalstage a solution containing the respective alkaline metal chloride, thesodium or potassium salt of atorvastatin and an excess of the usedalkaline hydroxide is obtained. It was surprisingly found out that byrepeated extraction of this solution with a suitable solvent, preferablyan ester of a C₁-C₅ acid and a C₁-C₅ alcohol, more preferably ethylacetate, the respective salt can almost quantitatively be transferred tothe organic phase and the latter can be used for further processing asdescribed above.

An X-ray difractogram of atorvastatin prepared by the proceduredescribed in the present invention is indicative of entirely amorphousstructure (see FIG. 2).

The invention is further illustrated in annexed drawings and in thefollowing examples. The examples, which illustrate preferablealternatives of the manufacture of atorvastatin of this invention, areof an illustrative character only and do not restrict the scope of theinvention in any respect.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts an X-ray difractogram of atorvastatin prepared by theprocedure described in U.S. Pat. No. 5,298,627.

FIG. 2 depicts an X-ray difractogram of atorvastatin prepared by theprocedure described in the present invention.

EXAMPLES Example 1

To the weighed ester of formula II (5 g, 7.6 mmol) tetrahydrofuran (75ml) is added and, after all the substance has dissolved, 10% HCl (17 ml)is added. The mixture is stirred at the laboratory temperature for 6hours. To the obtained solution a solution of 40% NaOH (10 ml) is addedin the course of 5 minutes so that the temperature does not exceed 35°C. and the heterogeneous mixture is stirred intensively for 15 hoursand, thereafter, poured into a separatory funnel containingdemineralised water (150 ml) and hexane (50 ml). After shaking, theorganic layer is removed and the aqueous layer is extracted with amixture of hexane (40 ml) and tetrahydrofuran (10 ml). After thecomplete separation, the aqueous layer is extracted with ethyl acetate(1×40 ml, 4×20 ml). The ethyl acetate extract is then gradually shaken 3times with demineralized water (5 ml), containing always 1 g of calciumacetate in 5 ml of water. The resulting ethyl acetate extract is washedwith demineralized water (2×5 ml), concentrated in a vacuum evaporatorto the volume of 20 ml. After filtration, the clear solution is addeddrop-wise to hexane (200 ml) under vigorous stirring over 5 minutes andthen the mixture is stirred for another 20 minutes, the insolublefraction is sucked away, washed with hexane (20 ml) and dried in vacuumat the laboratory temperature. 4.1 g of amorphous atorvastatin isobtained.

Example 2

Using the process described in Example 1, wherein potassium hydroxideinstead of sodium hydroxide was used for the hydrolysis of the ester,thus obtaining the potassium salt of atorvastatin, which was furtherprocessed according to the procedure described in Example 1.

Example 3

To the weighed ester of formula II (5 g, 7.6 mmol) tetrahydrofuran (75ml) is added and, after all the substance has dissolved, 10% HCl (17 ml)is added. The mixture is stirred at the laboratory temperature for 24hours. To the solution a solution of 40% NaOH (10 ml) is then added inthe course of 5 minutes and the heterogeneous mixture is stirredintensively for 17 hours and, thereafter, poured into a separatoryfunnel containing demineralised water (150 ml) and hexane (50 ml). Aftershaking, the organic layer is removed and the aqueous layer is extractedwith a mixture of hexane (40 ml) and tetrahydrofuran (10 ml). After thecomplete separation, the aqueous layer is extracted with ethyl acetate(1×40 ml, 3×20 ml). After evaporating the extract 4 g of the sodium saltof atorvastatin are obtained. After re-crystallizing from ethanol, thesalt is dissolved in ethyl acetate (100 ml) and the ethyl acetatesolution is gradually shaken 3 times with demineralized water (5 ml),containing always 1 g of calcium acetate in 5 ml of water. The resultingethyl acetate solution is washed with demineralized water (2×5 ml) and,after being dried with magnesium sulphate, it is concentrated in avacuum evaporator to the volume of 30 ml. After filtration, the clearsolution is added drop-wise to hexane (300 ml) under vigorous stirringover 5 minutes and then the mixture is stirred for another 20 minutes,the insoluble fraction is sucked away, washed with hexane (20 ml) anddried in vacuum at the laboratory temperature. 3.1 g of amorphousatorvastatin is obtained.

Example 4

To the weighed ester of formula II (5 g, 7.6 mmol) tetrahydrofuran (75ml) is added and, after all the substance has dissolved, 10% HCl (17 ml)is added. The mixture is stirred at the laboratory temperature for 24hours. To the solution a solution of 40% NaOH (10 ml) is then added inthe course of 5 minutes and the heterogeneous mixture is stirredintensively for 17 hours and, thereafter, poured into a separatoryfunnel containing demineralised water (150 ml) and hexane (50 ml). Theaqueous layer is acidified with 10% HCl to pH=3 and extracted with ethylacetate (4×20 ml). The obtained extract is mixed with a mixture ofcalcium hydroxide (0.87 g) in demineralized water (15 ml) for 20minutes. Then the aqueous layer is separated, the extract is washed withdemineralized water (2×5 ml) and dried with magnesium sulphate (10 g)for 1 hour. To the dried extract hexane (160 Ml) is added under stirringand the resulting insoluble fraction is sucked away after 1 hour. Afterdrying up, 3.3 g of amorphous atorvastatin is obtained.

Example 5

In the procedure described in Example 4, wherein a solution of calciummethanolate in methanol is used instead of calcium hydroxide for theconversion of the atorvastatin acid to its calcium salt, an analogousamount of amorphous atorvastatin is obtained after the processingdescribed in Example 4.

Example 6

The weighed quantity of the ester of formula II (8.7 g, 13.3 mmol) isadded to a round-shaped flask containing a mixture of tetrahydrofuran(100 ml) and 10% HCl (30 ml, 0.082 mol) under stirring and the resultingsolution is stirred at the laboratory temperature for 24 hrs.Thereafter, in the course of 15 minutes, a 30% solution of NaOH (24 ml,7.2 g, 0.18 mol) is added drop-wise to the solution; the reactionmixture will self-heat up and become cloudy. This mixture is stirred atthe laboratory temperature for 15 hours and, thereafter, it is pouredinto a separatory funnel containing hexane (100 ml) and demineralizedwater (300 ml). After thorough shaking and separation of layers thebottom aqueous layer is shaken with additional hexane (2×50 ml). Thewashed aqueous layer is acidified with 10% HCl to pH=4 and extractedwith dichloromethane (1×100 ml, 2×50 ml, 2×25 ml), the organic layer iswashed with saturated brine (2×25 ml) and dried with CaSO₄ (25 g)overnight. Thereafter, the desiccant was filtered away, washed with drydichloromethane (50 ml) and to the resulting solution a solution oftriethylamine (3 ml, 21.5 mmol) in dry dichloromethane (20 ml) is addedand the solution was evaporated to dryness in a rotary vacuum evaporatorafter stirring at the laboratory temperature for 0.5 hr. The resultingsolid foam (ca 10 to 11 g) was mixed with dry dichloromethane (25 ml)and evaporated to dryness again (ca 9 g). This procedure was repeatedonce more to obtain 8.34 g of yellowish solid foam of thetriethylammonium salt (12.6 mmol, 95%). The triethylammonium salt isdissolved in ethyl acetate (50 ml) and the solution is transferred to aseparatory funnel. A solution of calcium acetate monohydrate (1.2 g, 6.8mmol) in demineralized water (10 ml) is there added and the content ofthe separatory funnel is shaken. After the separation the aqueous layeris removed, the organic layer is shaken with water (2×10 ml) and driedwith magnesium sulphate. After the separation, the organic layer isdiluted with toluene (50 ml) and, under intensive stirring at thelaboratory temperature, hexane (25 ml) is added drop-wise. Thereafter,the temperature of the mixture is increased to 50° C. and the mixture isstirred at this temperature until the primarily formed turbidity hasbeen dissolved. Under intensive stirring, the temperature is let to dropspontaneously to 30° C. (some turbidity is formed again) and, at thistemperature, hexane (100 ml) is added drop-wise without any furtherheating. Thereafter, the mixture is stirred at the laboratorytemperature for another 10 minutes, the remaining quantity of hexane(100 ml) is added drop-wise and the mixture is stirred at the laboratorytemperature for 1 hr. Atorvastatin, separated in this way, is suckedaway, washed with hexane (25 ml), dried in vacuum up to constant weightand then triturated in an agate bowl. 5.6 g of amorphous atorvastatin isobtained.

Example 7

The weighed quantity of the ester of formula II (1 g) is added to amixture of tetrahydrofuran (20 ml) and 10% HCl (3.5 ml) under stirringand the resulting solution is stirred at the laboratory temperature for10 hrs. Thereafter, in the course of 15 minutes, a 40% solution of NaOH(2 ml) is added drop-wise to the solution and this mixture is stirred atthe laboratory temperature for 15 hrs and, thereafter, it is poured intoa separatory funnel containing hexane (10 ml) and demineralized water(30 ml). After thorough shaking and separation of layers the bottomaqueous layer is shaken with additional hexane (2×5 ml). The washedaqueous layer is acidified with 10% HCl to pH=4 and extracted withdiethyl ether (2×10 ml, 2×5 ml), the organic layer is washed withsaturated brine (2×5 ml) and dried with Na₂SO₄. Thereafter, thedesiccant was filtered away, washed with dry diethyl ether and to theresulting solution triethylamine (0.3 ml) is added and the solution wasevaporated to dryness in a rotary vacuum evaporator after stirring atthe laboratory temperature for 0.5 hr. The resulting solid foam wasmixed with dry diethyl ether (25 ml) and evaporated to dryness again (ca0.9 g). The triethylammonium salt is dissolved in ethyl acetate (10 ml)and the solution is transferred to a separatory funnel. A solution ofcalcium acetate monohydrate (0.13 g) in demineralized water (1 ml) isthere added and the content of the separatory funnel is shaken. Afterthe separation the aqueous layer is removed, the organic layer is shakenwith water. After the separation, pentane is added drop-wise to theorganic layer under intensive stirring at the laboratory temperature.After dropping of ca 3 ml of pentane the solution turns remarkablycloudy and the mixture is stirred at the laboratory temperature for 15minutes. Thereafter, additional 7.5 ml of pentane are rapidly addeddrop-wise, the mixture is stirred at the laboratory temperature for 1 hrand then left to stay overnight. Atorvastatin, separated in this way, issucked away, washed with pentane (2 ml), dried in the air until constantweight and then triturated in an agate bowl. 0.6 g of amorphousatorvastatin is obtained.

Example 8

Using the method described in Example 7, wherein ethyl acetate was usedinstead of diethyl ether for the extraction of the acid, an analogousamount of amorphous atorvastatin is obtained.

Example 9

Using the method described in Example 7, wherein hexane is used insteadof pentane for the precipitation, an analogous amount of amorphousatorvastatin is obtained.

Example 10

Using the method described in Example 7, wherein heptane is used insteadof pentane for the precipitation, an analogous amount of amorphousatorvastatin is obtained.

Example 11

Using the method described in Example 7, wherein cyclohexane is usedinstead of pentane for the precipitation, an analogous amount ofamorphous atorvastatin is obtained.

Example 12

Using the method described in Example 7, wherein diethyl ether is usedinstead of pentane for the precipitation, an analogous amount ofamorphous atorvastatin is obtained.

Example 13

Using the method described in Example 7, wherein diisopropyl ether isused instead of pentane for the precipitation, an analogous amount ofamorphous atorvastatin is obtained.

Example 14

Using the method described in Example 7, wherein tert-butyl methyl etheris used instead of pentane for the precipitation, an analogous amount ofamorphous atorvastatin is obtained.

Example 15

Using the method described in Example 7, wherein, prior to theprecipitation with hexane, the ethyl acetate solution of atorvastatin isdiluted with 5 ml of toluene.

Example 16

Using the method described in Example 7, wherein, prior to theprecipitation with hexane, the ethyl acetate solution of atorvastatin isdiluted with 3 ml of tert-butyl methyl ether.

Example 17

Using the method described in Example 7, wherein, prior to theprecipitation with hexane, the ethyl acetate solution of atorvastatin isdiluted with 10 ml of tetrahydrofuran.

Example 18

The weighed quantity of the ester of formula II (1 g) is added to amixture of tetrahydrofuran (15 ml) and 10% HCl (3.5 ml) under stirringand the resulting solution is stirred at the laboratory temperature for24 hrs. Thereafter, in the course of 15 minutes, a 40% solution of NaOH(2 ml) is added drop-wise to the solution and this mixture is stirred atthe laboratory temperature for 17 hrs and, thereafter, it is poured intoa separatory funnel containing hexane (10 ml) and demineralized water(30 ml). After thorough shaking and separation of layers the bottomaqueous layer is shaken with additional hexane (2×5 ml). The washedaqueous layer is acidified with 10% HCl to pH=4 and extracted withdichloromethane (1×10 ml, 2×5 ml), to the organic layer triethylamine(0.3 ml) is added and the layer is dried with MgSO₄. Thereafter, thedesiccant was filtered away, washed with dry dichloromethane and thecombined organic solutions were evaporated to dryness in a rotary vacuumevaporator until constant weight (ca 0.85 g). The triethylammonium saltis dissolved in ethyl acetate (10 ml) and the solution is transferred toa separatory funnel. A solution of calcium acetate monohydrate (0.13 g)in demineralized water (1 ml) is there added and the content of theseparatory funnel is shaken. After the separation the aqueous layer isremoved; the organic layer is shaken with water. After the separation,hexane is added drop-wise to the organic layer under intensive stirringat the laboratory temperature. Atorvastatin, separated in this way, issucked away, washed with hexane (2 ml), dried in vacuum until constantweight and then triturated in an agate bowl. 0.6 g of amorphousatorvastatin is obtained.

Example 19

To the weighed ester II (5 g, 7.6 mmol) tetrahydrofuran (75 ml) is addedand after all of the substance has dissolved, 10% HCl (17 ml) is added.The mixture is stirred at the laboratory temperature for 24 hrs.Thereafter, in the course of 5 minutes, a 40% solution of NaOH (10 ml)is added drop-wise to the solution and the heterogeneous mixture isstirred vigorosuly for 17 hrs and, thereafter, it is poured into aseparatory funnel containing demineralized water (150 ml) and hexane (50ml). After shaking and repeated extraction with hexane (50 ml) theaqueous layer is acidified with 5 ml of concentrated HCl and extractedwith ethyl acetate (4×20 ml). After washing with brine (2×10 ml)triethylamine (1.5 ml) is added to the ethyl acetate extract isgradually shaken 3× with demineralised water (10 ml), containing always1 g of calcium acetate in 10 ml of water. The resulting solution waswashed with demineralised water (2×5 ml) and dried with magnesiumsulphate (10 g) for 1 hour. Hexane (50 ml) is added to the dried extractunder stirring and the resulting insoluble fraction is sucked away afterstirring for 1 hour. Drying affords 3.35 g of amorphous atorvastatin.

Example 20

Using the method described in Example 19, wherein an equivalent amountof a 40% aqueous solution of methylamine is used instead oftriethylamine.

Example 21

Using the method described in Example 19, wherein an equivalent amountof a 35% aqueous solution of ammonia is used instead of triethylamine.

1. A method of manufacturing an amorphous form of the hemi-calcium saltof (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid of formula I

wherein (3R,5R) tert-butyl(6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetateof formula II

is first converted, in acidic hydrolysis, followed by alkalinehydrolysis, to a salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid with an alkali metal, which is then, after optional acidification,extracted into an organic solvent comprising at least one ester of C₁-C₅acids with C₁-C₅ alcohols, wherein it is, after purifying operations,converted by the treatment with a calcium salt or calcium hydroxide, ora calcium C₁-C₅ alcoholate, to the hemi-calcium salt, and the latter isprecipitated with a C₅-C₁₂ hydrocarbon or a dialkylether of formulaR₁OR₂, wherein each of R₁ and R₂ is a C₁-C₅ alkyl group.
 2. The methodaccording to claim 1 wherein the solution of the salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid with the alkali metal cation, prepared from the compound of formulaII, containing excess chloride and hydroxide of the respective cation,is acidified and extracted to give a solution of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid, which is further converted, by reacting with calcium hydroxide ora calcium alcoholate, to a solution of the hemi-calcium salt.
 3. Themethod according to claim 1, wherein the solution of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid in the respective ester of a C₁-C₅ acid with a C₁-C₅ alcohol isconverted to an alkali metal salt.
 4. The method according to claim 1,wherein the hemi-calcium salt is precipitated from a solution of ethylacetate.
 5. The method according to claim 1, wherein the precipitationis carried out by adding at least one non-polar solvent selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, and adialkylether of formula R₁OR₂, wherein each of R₁ and R₂ is a C₁-C₅alkyl group, to a solution of the hemi-calcium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid in the respective solvent.
 6. The method according to claim 1,wherein the solution of the hemi-calcium salt of (3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid in the ester of a C₁-C₅ acid with a C₁-C₅ alcohol is added to atleast one non-polar solvent selected from the group consisting ofpentane, hexane, heptane, cyclohexane, and dialkylether of formula R₁OR₂, wherein each of R₁ and R₂ is a C₁-C₅ alkyl group.
 7. The methodaccording to claim 1, wherein the solution of the hemi-calcium salt of(3R,5R)7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid in the respective ester is diluted, prior to precipitation, with 5to 95%, of a suitable co-solvent.
 8. The method according to claim 7wherein toluene, t-butyl-methylether or tetrahydrofuran is used as theco-solvent.